Human cytomegalovirus (HCMV) is a widespread pathogen that is the leading viral cause of birth defects and a major cause of morbidity and mortality in adults who are immunocompromised. It is a life-threatening, opportunistic infection in AIDS and a common post-transplant complication in allograft recipients. The long-term goal of this research program is to elucidate at the molecular level the function of HCMV genes that regulate the interaction of the virus with its host and thereby control the processes of viral replication and pathogenesis. This proposal is focused on the function of two HCMV proteins that are delivered to the infected cell as constituents of the virion. These proteins are encoded by the UL69 and UL82 genes of HCMV. The products of these genes have been shown to activate transcription of viral and cellular genes. Further, UL69 can block cell cycle progression in the G1 compartment and preliminary studies indicate that UL82 also modulates cell cycle progression. Mutant viruses will be constructed lacking the coding regions for these genes, their phenotypes will be characterized, the biochemical basis for the activities of these proteins will be explored, and the mechanism by which these proteins are directed to be packaged in the virion will be investigated.